Despite modest success of behavior-based therapy in treating Post Traumatic Disorder Stress (PTSD), there is still considerable room for improvement especially among special groups including combat veterans that have been resistant to both behavioral and pharmacological therapy. Current animal models of PTSD are based on learning theories where cues associated with traumatic stress are thought to elicit stress reactions. However, in addition to exaggerated reactions to the cues associated with trauma, another core feature of PTSD is exaggerated behavioral and physiological responding to stressful events themselves. We have shown that reflexes such as the rabbit eyeblink and heart rate can become quite exaggerated as a result of learning and these changes can be observed when the reflex is tested by itself. This phenomenon is called conditioning-specific reflex modification (CRM) and demonstrates traits that are comparable to the PTSD symptoms of exaggerated behavioral and physiological responding to stressful events. We propose that exaggerated responding to stress and the cues associated with stress may constitute an endophenotype of PTSD. Our experiments show that conditioned responses as well as CRM can both be dramatically reduced by presenting the cues and the stressful event in an explicitly unpaired manner. However, no all animals extinguish. We propose that a failure to extinguish may constitute a second endophenotype of PTSD. The hypothesis on which the current proposal is based is that reversing the responses to cues associated with trauma as well as the reactions to trauma itself may provide a better means of reversing two core features of PTSD than current therapies. The current proposal tests this hypothesis with two specific aims that will determine the behavioral and physiological characteristics of unpaired CRM extinction that may predict psychotherapeutic approaches to PTSD (Specific Aim 1) and locate and examine neural substrates for CRM extinction that may develop pharmacological targets for the treatment of PTSD (Specific Aim 2). Both the conditioned responses and the conditioning-specific changes in the reflex studied here may provide a more comprehensive animal model of core features of PTSD than those currently available and help provide new treatment strategies for the disorder. The research is therefore relevant to public health because it may provide preventive and therapeutic interventions for the growing numbers of persons in this country with stress-related disorders in learning and memory, particularly PTSD, as well as provide an understanding of the biological processes that underlie learning and memory. PUBLIC HEALTH RELEVANCE: Disorders of learning and memory have profound consequences for the individual and result in an enormous cost to society. We have found that once a strong association is formed between a stimulus and a stressful event, weaker versions of that stimulus can trigger the reaction to the original stressor in its full-blown or even exaggerated form. This is similar to disorders such as PTSD where intense distress results from exposure to a stressor or trauma and the cues associated with that event. We hypothesize that we can significantly reduce both these reactions with an explicitly unpaired extinction procedure leading to a better animal model of PTSD and better treatment strategies for the disorder. The information obtained from the current proposal will be important for understanding and developing strategies to treat disorders where reactions to stressors are exaggerated as a result of traumatic experience.